Although it has been known for over a century that chloroform causes kidney necrosis in man and animals, the molecular basis for this toxicity has been elusive. The results of this study, however, indicate that the nephrotoxicity of chloroform is due to its renal metabolism to the toxic metabolite phosgene (COCl2). Variations in the rate of this reaction correlate with difference in susceptibility to CHCl3-induced nephrotoxicity. For example, DBA/2J male mice are more sensitive to CHCl3-induced nephrotoxicity and their kidney homogenates metabolize CHCl3 to COCl2 more rapidly than do DBA/2J female mice, ICR male mice and C57/BL6 male mice. The enzyme in the kidney that metabolizes chloroform to phosgene remains to be determined as well as its location in the kidney and its physiological function.